The main objective of Core 9003 is to generated transgenic mice that are instrumental for Projects 4 and 5; to understand the role of neurotrophic factors, cholinergic and glutabminergic pathways in learning and memory, all of which are relevant to the biology of Alzheimer~s Disease. Furthermore these mice will facilitate Project 1 to develop a better gene transfer system in the brain. We will produce transgenic mice via microinjecting DNA into the pronucleus of one-cell embryos and gene targeting in mouse embryonic stem (ES) cells. We will be assisted by Core 9001 in the production of adenoviruses expressing the Cre recombinase that will be used to generate conditional mutant ES cell clones. The specific aims are: 1. To generate transgenic mice by DNA microinjection. 2. To test reagents, maintain ES cell lines, and generate feeder cells for cultivating embryos and ES cells. 3. To generate null and conditional mutant ES cell lines by homologous recombination. 4. To generate chimeras for establishing germ- line mutant mice on an outbred or 129 inbred genetic background.